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This is a multi-site, double-blinded, two-arm, two:one, randomized, trial comparing the safety of an intramuscular (IM) injection of TMC278 LA to a placebo given once every eight weeks over a 40 week period among sexually active, HIV- uninfected women.

Condition or disease

Intervention/treatment

Phase

Human Immunodeficiency Virus (HIV)

Drug: RilpivirineDrug: Placebo

Phase 2

Detailed Description:

This is a multi-site, double-blinded, two-arm, two:one randomized, placebo-controlled trial comparing the safety of TMC278 LA for 48 weeks after the initial 1M injection to a saline (0.9%NaCI) placebo IM injection among sexually active, HIV-uninfected women who are assessed by the clinic staff as being at "low risk" for HIV acquisition (in keeping with a safety trial). Approximately 132 women will be randomized to TMC278 LA and placebo in approximately a two:one ratio (88 and 44 in the TMC278 LA and placebo arm, respectively).

Approximately 96 women will be enrolled in SSA and approximately 36 women will be enrolled in the US. In order to screen for initial safety and tolerability of the active product, a run-in period with oral rilpivirine will precede the injection of TMC278 LA. Participants randomized to the placebo arm will receive oral placebo capsules prior to injection of saline solution (0.9%NaCI). Participants will be observed while taking the study product by site staff on approximately six occasions during the first two weeks of the oral run-in at Week 0 (Enrollment), at Week 2 (Oral Run-in Safety Visit), and on four separate DOT visits between Weeks 0 and 2. Cervicovaginal and rectal fluid will be collected for PK studies at a single follow-up visit. A subset of approximately 24 women at US sites will have vaginal tissue collection for PK studies at a single follow-up visit (Tissue Subset).

Participants who present with Grade 2 or greater RELATED AEs during the oral-run in phase will not receive the injectable TMC278 LA. Participants who present with Grade 3 or 4 UNRELATED AEs will not proceed to the injectable phase unless approved by the Clinical Management Committee (CMC).

Arm 1: Participants randomized to the active arm will receive rilpivirine 25 mg capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of TMC278 LA, 1200 mg dose, at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion 1200 mg of TMC278 LA will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections).

Arm 2: Participants randomized to the placebo arm will receive placebo capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of saline (0.9% NaCI) at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion placebo will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections).

Arm 1: Participants randomized to the active arm will receive rilpivirine 25 mg capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of TMC278 LA, 1200 mg dose, at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion 1200 mg of TMC278 LA will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections).

Drug: Rilpivirine

Rilpivirine (TMC278), a non-nucleoside reverse transcriptase inhibitor (NNRTI) is a substituted diaryl-pyrimidine (DAPY) derivative with potent antiviral activity against HIV. It is approved by the US FDA for once daily oral administration and is effective as part of treatment for ARV-na'ive HIV-infected patients as rilpivirine 25 mg capsules. It is also co-formulated with TDF and FTC for use as a once- daily single fixed-dose combination (Complera™).

Placebo Comparator: Placebo

Arm 2: Participants randomized to the placebo arm will receive placebo capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of saline (0.9% NaCI) at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion placebo will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections).

Drug: Placebo

Participants randomized to the placebo arm will receive oral placebo capsules prior to injection of saline solution (0.9%NaCI). Participants will be observed while taking the study product by site staff on approximately six occasions during the first two weeks of the oral run-in at Week 0 (Enrollment), at Week 2 (Oral Run-in Safety Visit), and on four separate DOT visits between Weeks 0 and 2. Cervicovaginal and rectal fluid will be collected for PK studies at a single follow-up visit.

Number of participants experiencing any Grade 2 or higher clinical and laboratory AEs to evaluate the safety of the injectable product, TMC278 LA (1200 mg dose administered at Weeks 4, 12, 20, 28, 36 and 44), through 48 weeks after initial injection (at Week 52) in women in SSA and the US.

Secondary Outcome Measures
:

TMC278 LA Brief Questionnaires [ Time Frame: Up to 76 weeks ]

Tolerability (Acceptability) of TMC278 LA to evaluate proportion of participants who do not receive the full regimen of injections due to an AE will be calculated for the women in the TMC278 LA product arm. If the observed tolerability is 90%, the 95% Cl will be 81.5% to 94.8%.

Patient Plasma Analyzed for TMC278 and metabolites [ Time Frame: Up to 76 weeks ]

Plasma samples will be used to describe the pre-dose TMC278 drug concentrations during both the oral and injectable dosing phases.

Patient Fluid Concentrations [ Time Frame: Up to 76 weeks ]

•To describe TMC278 LA concentration in cervicovaginal fluid and rectal fluid in participants, and in cervicovaginal tissue in a subset of approximately 24 participants (US sites only).

Patient Rilpivirine Testing [ Time Frame: Up to 76 weeks ]

•To evaluate the safety of rilpivirine (oral+ injectable LA product) through Week 76 in women in SSA and the US.

Observed Incidence Rates [ Time Frame: Up to 76 weeks ]

The HIV incidence rate in each arm will be estimated. The precision with which the true HIV incidence rate can be estimated from the observed data depends on the length of follow-up period and the sample size. Two-sided 95% Cis for the true HIV incidence rate in each arm based on observing a particular numbers of HIV infections in each arm over the 76 week study duration are shown in Table 7. Calculations are done using Poisson rate Cl calculation method.27

Rate of TMC278 in Vaginal Fluid, Vaginal Tissue and Rectal Fluid [ Time Frame: Up to 44 weeks ]

Vaginal fluid, vaginal tissue, and rectal fluid samples collected at Week 36 (preferred) or Week 44 will be used to describe concentrations of TMC278 in the sampled anatomic compartments that would represent trough (pre-dose) concentrations well into what is anticipated to be the steady-state period. TMC278 parent to metabolite ratios in each anatomic compartment will also be described.

Pharmacogenomic Analysis of the Expression of Drug Metabolizing Enzymes [ Time Frame: Up to 76 weeks ]

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Ages Eligible for Study:

18 Years to 45 Years (Adult)

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

Criteria

Inclusion Criteria: Women who meet all of the following criteria will be eligible for inclusion in the study:

Women, 18- 45 years (inclusive) of age at Enrollment

Female at birth

Willing and able to provide informed consent to take part in the study

Willing and able to provide adequate locator information

Willing and able to provide acceptability and adherence assessments throughout the study

Understands and agrees to local reporting requirements for sexually transmitted infections (STis)

No evidence of an active STI, women who have an STI (Chlamydia trachomatis (CT), Neisseria gonorrhoeae (GC), or syphilis) identified at the Screening visit are ineligible*

Per participant report, no diagnosis of GC, CT, or syphilis in the last 6 months

Availability to return for all study visits and participate in all study-related procedures, barring unforeseen circumstances

Per participant report, using (or willing to use) an acceptable form of contraception (e.g., intrauterine device [IUD], hormonal contraception [DMPA], oral, injectable, transdermal patch, implants) from screening until one month after last study visit or surgical sterilization of the participant

Must agree to use condoms for the duration of the study

Must agree not to participate in other concurrent drug or vaccine trials

Women who have an STI identified at the Screening visit (CT, GC, or syphilis) will be provided treatment but are ineligible. Women who report having CT, GC, or syphilis in the last six months are ineligible.

Specimens for Screening labs must be obtained within 28 days prior to study Enrollment.

3.1.1 Inclusion Criteria for the Tissue Subset (US sites only) A subset of approximately 24 participants at US sites will participate in more intensive sampling of vaginal tissue during Week 36 (preferred) or Week 44.

For these participants, the following additional criteria need to be met:

•Satisfactory Pap results in the 12 calendar months prior to biopsy consistent with Grade 0 according to the Female Genital Grading Table for Use in Microbicide Studies Addendum 1 to the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 1.0, December 2004 (Clarification dated August 2009), or satisfactory evaluation with no treatment required of Grade 1 or higher Pap result per American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines in the 12 calendar months prior to biopsy is required, as indicated.

If there is no documentation of satisfactory Pap results, and if indicated, the participant should be offered to have the test performed by the site prior to enrollment in the Tissue Subset. If Pap testing is indicated and participants decline, they are not eligible for the Tissue Subset.

In addition to documentation of satisfactory Pap results, women must have normal laboratory results for coagulation tests to be eligible for the Tissue Subset. Abnormal coagulation test results may indicate an increased risk of bleeding.

Women have to be willing to abstain from vaginal intercourse and practices involving insertion of anything in the vagina (drug, douche, penis, or sex toy) for 3 days prior to vaginal biopsy and for 7 days post-biopsy, to minimize risk of HIV-1 infection and bleeding complications after the procedure.

Participants must not be pregnant at the time of vaginal sampling, based on pregnancy test results from previous visits and on the result of urine pregnancy test performed on the same day before the proposed vaginal sampling.

Women undergoing biopsy must have received all prior injections of study product, in accordance with the protocol, to be eligible for inclusion.

Exclusion Criteria: Women who meet any of the following criteria will be excluded from the study:

Experiencing early menopause using clinical criteria (amenorrhea greater than six months in absence of pregnancy) or a prior report of an abnormal Follicle Stimulating Hormone (FSH) test

PrEP or post-exposure prophylaxis (PEP) for HIV exposure within 90 days prior to Screening

Pregnant or last pregnancy outcome 90 days or less prior to Screening

Currently breastfeeding

Intends to become pregnant during the period of study participation

Experiencing uncontrolled depression or active suicidal ideation

History of recurrent urticaria

Any history of anaphylaxis or severe allergy resulting in angioedema

Any serious acute, chronic, or progressive disease (e.g. known history of neoplasm, cancer, insulin-dependent diabetes, cardiac disease, auto-immune disease), or with signs of cardiac disease, renal failure, or severe malnutrition

Any laboratory abnormalities that are Grade 2 or higher, according to the DAIDS Toxicology tables (please see Section 6.1 for a list of Screening laboratory tests)

Recreational injection drug use in the 52 weeks prior to screening

Participating or plans to participate in another research study involving study drugs, vaccines or medical devices

Participated in another research study involving study drugs, vaccines or medical devices within the four weeks prior to screening; may be longer than four weeks depending on half-life of study drug

Past participation in an HIV vaccine study

Has plans to relocate and cannot attend the visits at the clinic

Per participant report at Screening, current or anticipated ongoing use and/or unwillingness to abstain from contraindicated medications or supplements (listed in the SSP Manual)

History of additional risk factors for Torsade de Pointes (TdP), such as heart failure, hypokalemia, hypomagnesia, family history of known long QT syndrome, or sudden death at young age (S 40 years) in a first-degree relative (i.e., biological parent, sibling, or offspring)

Currently active Tuberculosis (TB), or undergoing treatment for the same (by self-report)

Any reactive or positive HIV test at Screening or Enrollment, even if the person is confirmed to be HIV-uninfected

Has any other condition that, in the opinion of the site loR or designee, would preclude informed consent, make study participation unsafe, interfere with adherence, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives (e.g., at increased risk of cardiovascular vents)

Women who do not meet eligibility criteria because of an abnormal EKG, risk factors for TdP, an STI (GC, CT, or syphilis) present at Screening or report of an STI (GC, CT, or syphilis) in the past 6 months, or a history of arrhythmia may not be re-screened.

Women who present at Screening with symptoms consistent with an acute HIV infection or who have a reactive HIV test may not be re-screened. Women who do not meet eligibility criteria for the study for other reason(s) may be re-screened at a future date at the discretion of the site loR.

3.2.1 Exclusion Criteria for the Tissue Subset (US sites only)

Participants of the Tissue Subset must meet the above eligibility criteria to be enrolled in HPTN 076. Participants interested in participating in the Tissue Subset must meet additional inclusion and exclusion criteria. Women who meet any of the following criteria will be excluded from the Tissue Subset:

Unwillingness to abstain from the following medications for a period of 10 days before a biopsy procedure:

Aspirin*

Non-steroidal anti-inflammatory drugs (NSAIDS)

*Daily use of low-dose aspirin (no more than 81 mg) is allowed at the discretion of the loR.

Unwillingness to abstain from the following medications for 3 days prior to vaginal biopsy and for 7 days post-biopsy: Heparin, including Lovenox®, Warfarin, Plavix® (clopidogrel bisulfate), and any other drugs that are associated with increased risk of bleeding following biopsy procedures at the discretion of the loR.

Carcinoma in situ of the cervix or invasive cervical cancer. Abnormalities of the vaginal mucosa or significant vaginal symptom(s), which in the opinion of the loR represent a contraindication to biopsy (including but not limited to presence of any unresolved injury, and infectious or inflammatory condition of the local mucosa).